CN104804002B - Synthesis method for 9H-pyrimido(4,5-b) indole compounds - Google Patents

Synthesis method for 9H-pyrimido(4,5-b) indole compounds Download PDF

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CN104804002B
CN104804002B CN201510161043.2A CN201510161043A CN104804002B CN 104804002 B CN104804002 B CN 104804002B CN 201510161043 A CN201510161043 A CN 201510161043A CN 104804002 B CN104804002 B CN 104804002B
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mmol
pyrimido
indole
nmr
mhz
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CN104804002A (en
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范学森
李彬
张新迎
郭胜海
张举
沈娜娜
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Henan Normal University
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Henan Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention discloses a synthesis method for 9H-pyrimido(4,5-b) indole compounds, and belongs to the technical field of organic synthesis. The synthesis method is characterized by comprising the following steps: dissolving 1-bromine-2-(2,2-dibromoethylene)benzene or derivatives of 1-bromine-2-(2,2-dibromoethylene)benzene, ammonia water and aldehyde compounds in an organic solvent; adding catalyst transitional metal salt and an additive; under the presence of air, carrying out a reaction at 60-100 DEG C to obtain the 9H-pyrimido(4,5-b) indole compounds. According to the synthesis method, a synthesis process is a one-pot multi-component series reaction; the operation is simple and convenient; the resource waste and environmental pollution caused by the problems such as the utilization of various reagents in multi-step reactions, and the purification treatment on reaction intermediates in all the steps, are avoided. Therefore, the synthesis method is economical, practical, environmental-friendly and novel for synthesis of the 9H-pyrimido(4,5-b) indole compounds.

Description

A kind of 9h- pyrimido [4,5-b] Benzazole compounds synthetic method
Technical field
The invention belongs to technical field of organic synthesis is and in particular to a kind of 9h- pyrimido [4,5-b] Benzazole compounds Synthetic method.
Background technology
Indole and its derivant are a kind of alkaloids being widely present in nature.Due to such compound have various Biological activity, so be constantly subjected to chemist and the extensive concern of medicine scholar for many years.In numerous indole derivativeses, 9h - pyrimido [4,5-b] indole be many function micromolecular compounds important feature unit.In addition, with 9h- pyrimido [4,5-b] indole synthesize for base obtain base extension nucleoside, be also successfully introduced in oligonucleotide, and be used as biology Probe is to study space structure and the performance of dna.With regard to 9h- pyrimido [4,5-b] Benzazole compounds synthesis, existing Method is mainly obtained by carrying out functional group on existing indole skeleton, and this not only makes the scope of reaction substrate be limited System, and improve cost of material, it is unfavorable for that it is applied in actual production.In view of 9h- pyrimido [4,5-b] indole The importance of class compound, development further synthesizes efficient, the economic new method of such compound and has great importance.
Content of the invention
Present invention solves the technical problem that there is provided a kind of 9h- pyrimido [4,5-b] Benzazole compounds synthesis side Method, this synthetic method, from the raw material of simply easily preparation, by one pot of multicomponent cascade reaction, directly obtains 9h- pyrimido [4,5-b] Benzazole compounds, in one pot reaction, construct out indole ring and pyrimidine ring, combined coefficient is high, condition temperature simultaneously With, easy to operate, wide application range of substrates, it is suitable for industrialized production.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, a kind of 9h- pyrimido [4,5-b] indoles The synthetic method of compound it is characterised in that: by bromo- for 1- 2-(2,2- dibromo vinyl) benzene or derivatives thereof, ammonia and aldehydes Compound is dissolved in organic solvent, is subsequently adding catalyst transition metal salt and additive, in the presence of the air in 60-100 DEG C Reaction is obtained 9h- pyrimidine [4,5-b] Benzazole compounds, the reaction equation in this synthetic method is:
Wherein r1For hydrogen, fluorine, chlorine, trifluoromethyl, methyl or methoxy, r2For 1- naphthyl, 2- thienyl, phenyl or replacement Phenyl, the substituent group on this substituted-phenyl phenyl ring is one or more of fluorine, chlorine, bromine, methyl, trifluoromethyl or methoxyl group, The position of substituent group is the ortho position on phenyl ring, meta or para position, and organic solvent is dimethyl sulfoxide, n, n- dimethylformamide, Methyl pyrrolidone, isopropanol or dioxane, catalyst transition metal salt is Cu-lyt., cuprous bromide, Hydro-Giene (Water Science)., second Sour copper or copper chloride, additive is one of 1,10- phenanthroline, l- proline, triethylene diamine or trimethylace tonitric or many Kind.
Limit further, the bromo- 2-(2 of described 1-, 2- dibromo vinyl) benzene or derivatives thereof, ammonia and aldehyde compound The amount of the material that feeds intake ratio be 1:7-42:2-3.
The present invention compared with prior art has the advantage that (1) building-up process is one pot of multicomponent cascade reaction, operation Easy, it is to avoid due in multistep reaction plurality of reagents using and purification process to each step reaction intermediate etc. cause The wasting of resources and environmental pollution；(2) building-up process is one pot of multicomponent cascade reaction, constructs out indole in one pot reaction simultaneously Ring and pyrimidine ring, combined coefficient is high；(3) raw materials used cheap and easy to get or raw material is easily prepared；(4) reaction is below 100 DEG C Carry out, mild condition, easy and simple to handle；(5) substrate is applied widely.Therefore, the present invention is 9h- pyrimido [4,5-b] indole The synthesis of class compound provides a kind of economical and practical and environmental protection new method.
Specific embodiment
By the following examples the above of the present invention is described in further details, but this should not be interpreted as this The scope inventing above-mentioned theme is only limitted to below example, all belongs to this based on the technology that the above of the present invention is realized Bright scope.
Embodiment 1
Add 1a (0.5 mmol, 170 mg), 2a (1.5 mmol, 159 mg) in the reaction tube of 25 ml, iodate is sub- Copper (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylace tonitric (0.5 mmol, 51 Mg) and n, n- dimethylformamide (3 ml), it is subsequently adding strong aqua ammonia (7 mmol, 0.5 ml).It is heated to 80 under air DEG C, after stirring 30 hours, add 5 ml saturated ammonium chloride solutions that reaction is quenched, be extracted with ethyl acetate (10 ml × 2), it Organic phase washed with water and saturated aqueous common salt wash successively afterwards, anhydrous sodium sulfate drying.Filter, be spin-dried for, cross silica gel post separation (oil Ether/ethyl acetate=10/1) obtain white solid product 2,4- diphenyl -9h- pyrimido [4,5-b] indole 3a(88 mg, 55%).The characterize data of this compound is as follows:1h nmr (400 mhz, dmso-d 6) δ: 7.18 (t,j= 7.2 hz, 1h), 7.47-7.58 (m, 5h), 7.66 (d,j= 7.2 hz, 3h), 7.81 (d,j= 7.6 hz, 1h), 8.01 (d,j= 6.4 hz, 2h), 8.55 (d,j= 6.0 hz, 2h), 12.56 (s, 1h).13c nmr (100 mhz, dmso-d 6) δ: 109.4, 112.4, 119.3, 121.2, 122.3, 128.0, 128.3, 129.0, 129.3, 129.4, 130.5, 130.7, 138.6, 139.1, 139.6, 157.7, 159.6, 159.9. ms: m/z 322 [mh]+.
Embodiment 2
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2a (1.5 in the reaction tube of 25 ml Mmol, 159 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 Ml).It is heated to 100 DEG C under air, after stirring 30 hours, obtain product 2,4- diphenyl -9h- pyrimido [4,5-b] indole 3a (45 mg, 42%).
Embodiment 3
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2a (1.5 in the reaction tube of 25 ml Mmol, 159 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and dimethyl sulfoxide (3 ml), are subsequently adding strong aqua ammonia (7 mmol, 0.5 ml).In sky It is heated to 80 DEG C under gas, after stirring 30 hours, obtain product 2,4- diphenyl -9h- pyrimido [4,5-b] indole 3a(54 mg, 50%).
Embodiment 4
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2a (1.5 in the reaction tube of 25 ml Mmol, 159 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and isopropanol (3 ml), are subsequently adding strong aqua ammonia (7 mmol, 0.5 ml).Under air It is heated to 80 DEG C, after stirring 30 hours, obtain product 2,4- diphenyl -9h- pyrimido [4,5-b] indole 3a(40 mg, 37%).
Embodiment 5
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2a (1.5 in the reaction tube of 25 ml Mmol, 159 mg), Cu-lyt. (0.05 mmol, 4.9 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 Ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain product 2,4- diphenyl -9h- pyrimido [4,5-b] indole 3a (46 mg, 43%).
Embodiment 6
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2a (1.5 in the reaction tube of 25 ml Mmol, 159 mg), cuprous bromide (0.05 mmol, 7.2 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 Ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain product 2,4- diphenyl -9h- pyrimido [4,5-b] indole 3a (51 mg, 48%).
Embodiment 7
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2a (1.5 in the reaction tube of 25 ml Mmol, 159 mg), copper acetate (0.05 mmol, 9.1 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethyl Acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), it is subsequently adding strong aqua ammonia (7 mmol, 0.5 ml). It is heated to 60 DEG C under air, after stirring 30 hours, obtain product 2,4- diphenyl -9h- pyrimido [4,5-b] indole 3a(31 Mg, 29%).
Embodiment 8
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2a (1.5 in the reaction tube of 25 ml Mmol, 159 mg), copper chloride (0.05 mmol, 6.8 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethyl Acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), it is subsequently adding strong aqua ammonia (7 mmol, 0.5 ml). It is heated to 80 DEG C under air, after stirring 30 hours, obtain product 2,4- diphenyl -9h- pyrimido [4,5-b] indole 3a(34 Mg, 32%).
Embodiment 9
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2a in the reaction tube of 25 ml (1.5 mmol, 159 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), Trimethylace tonitric (0.5 mmol, 51 mg) and n, n- dimethylformamide (6 ml), be subsequently adding strong aqua ammonia (14 mmol, 1 Ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain product 2,4- diphenyl -9h- pyrimido [4,5-b] indole 3a (51 mg, 47%).
Embodiment 10
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2a (1.5 in the reaction tube of 25 ml Mmol, 159 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (1.5 ml), be subsequently adding strong aqua ammonia (3.5 mmol, 0.25 ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain product 2,4- diphenyl -9h- pyrimido [4,5-b] Yin Diindyl 3a(38 mg, 35%).
Embodiment 11
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2a (1 in the reaction tube of 25 ml Mmol, 106 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), 1,10- phenanthroline (0.1 mmol, 18.0 mg) and n, N- dimethylformamide (3 ml), is subsequently adding strong aqua ammonia (21 mmol, 1.5 ml).It is heated to 80 DEG C under air, stirring After 30 hours, obtain product 2,4- diphenyl -9h- pyrimido [4,5-b] indole 3a(26 mg, 24%).
Embodiment 12
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2a (1 in the reaction tube of 25 ml Mmol, 106 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), l- proline (0.1 mmol, 11.5 mg) and n, n- bis- Methylformamide (3 ml), is subsequently adding strong aqua ammonia (21 mmol, 1.5 ml).It is heated to 80 DEG C under air, stirring 30 is little Shi Hou, obtains product 2,4- diphenyl -9h- pyrimido [4,5-b] indole 3a(26 mg, 24%).
Embodiment 13
Method as described in embodiment 1, adds 1b (0.5 mmol, 179 mg), 2a (1.5 in the reaction tube of 25 ml Mmol, 159 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 Ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain white solid product 6- fluoro- 2,4- diphenyl -9h- pyrimido [4,5-b] indole 3b(94 mg, 56%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is as follows:1h nmr (400 mhz, dmso-d 6) δ: 7.35-7.45 (m, 2h), 7.52-7.60 (m, 4h), 7.66-7.71 (m, 3h), 7.99 (d,j= 5.6 hz, 2h), 8.53-8.55 (m, 2h), 12.61 (s, 1h).13c nmr (100 mhz, dmso-d 6) δ: 107.7, 108.0, 109.3, 113.6, 113.7, 115.6, 115.9, 119.8, 119.9, 128.4, 129.1, 129.27, 129.34, 130.8, 130.9, 136.1, 138.4, 138.7, 156.3, 158.3, 160.3, 160.4. hrms calcd for c22h15fn3: 340.1250 [m + h], found: 340.1242.
Embodiment 14
Method as described in embodiment 1, adds 1c (0.5 mmol, 188 mg), 2a (1.5 in the reaction tube of 25 ml Mmol, 159 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 Ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain white solid product 6- chloro- 2,4- diphenyl -9h- pyrimido [4,5-b] indole 3c(103 mg, 58%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is as follows:1h nmr (400 mhz, dmso-d 6) δ: 7.48-7.67 (m, 9h), 7.98 (d,j= 5.6 hz, 2h), 8.53 (d,j= 5.6 hz, 2h), 12.69 (s, 1h).13c nmr (100 mhz, dmso-d 6) δ: 108.8, 114.0, 120.7, 121.4, 125.3, 127.8, 128.4, 129.1, 129.27, 129.30, 130.8, 130.9, 138.1, 138.3, 138.7, 158.0, 160.3, 160.5. hrms calcd for c22h15cln3: 356.0954 [m + h], found: 356.0958.
Embodiment 15
Method as described in embodiment 1, adds 1d (0.5 mmol, 204 mg), 2a (1.5 in the reaction tube of 25 ml Mmol, 159 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 Ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain white solid product 6- trifluoromethyl -2,4- diphenyl -9h- Pyrimido [4,5-b] indole 3d(110 mg, 57%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is such as Under:1h nmr (400 mhz, dmso-d 6) δ: 7.53-7.54 (m, 3h), 7.56-7.71 (m, 3h), 7.76 (d,j= 8.8 hz, 1h), 7.81-7.83 (m, 1h), 8.02-8.05 (m, 3h), 8.54-8.57 (m, 2h), 12.98 (s, 1h).13c nmr (100 mhz, dmso-d 6) δ: 109.2, 113.3, 119.10, 119.14, 119.2, 121.5, 121.8, 123.9, 124.5, 126.6, 128.4, 128.5, 129.1, 129.30, 129.33, 131.0, 131.1, 132.0, 138.2, 138.6, 141.7, 158.6, 160.6, 160.9. hrms calcd for c23h15f3n3: 390.1218 [m + h], found: 390.1200.
Embodiment 16
Method as described in embodiment 1, adds 1e (0.5 mmol, 185 mg), 2a (1.5 in the reaction tube of 25 ml Mmol, 159 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 Ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain white solid product 6- methoxyl group -2,4- diphenyl -9h- phonetic Pyridine simultaneously [4,5-b] indole 3e(88 mg, 50%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is as follows :1h nmr (400 mhz, dmso-d 6) δ: 3.68 (s, 3h), 7.14-7.17 (m, 1h), 7.27 (s, 1h), 7.49-7.55 (m, 4h), 7.65-7.71 (m, 3h), 8.02 (d,j= 7.2 hz, 2h), 8.54 (d,j= 6.0 hz, 2h), 12.38 (s, 1h).13c nmr (100 mhz, dmso-d 6) δ: 55.8, 105.8, 109.4, 113.2, 116.5, 119.8, 128.3, 129.0, 129.1, 129.4, 130.6, 130.7, 134.2, 138.6, 138.8, 154.4, 157.8, 159.6, 159.7. hrms calcd for c23h18n3o: 352.1450 [m + h], found: 352.1458.
Embodiment 17
Method as described in embodiment 1, adds 1f (0.5 mmol, 177 mg), 2a in the reaction tube of 25 ml (1.5 mmol, 159 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), Trimethylace tonitric (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 Ml).It is heated to 80 under airoC, after stirring 30 hours, obtains white solid product 7- methyl -2,4- diphenyl -9h- pyrimidine And [4,5-b] indole 3f(90 mg, 54%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is as follows:1h nmr (400 mhz, dmso-d 6) δ: 2.46 (s, 3h), 7.01 (d,j= 8.0 hz, 1h), 7.37 (s, 1h), 7.53 (d,j= 7.6 hz, 3h), 7.65-7.70 (m, 4h), 8.01 (d,j= 6.4 hz, 2h), 8.54 (d,j= 6.4 hz, 2h), 12.42 (s, 1h).13c nmr (100 mhz, dmso-d 6) δ: 22.0, 109.5, 112.4, 116.9, 122.1, 122.7, 128.2, 129.0, 129.2, 129.3, 130.5, 130.6, 138.0, 138.6, 139.1, 140.1, 157.8, 158.9, 159.5. hrms calcd for c23h18n3: 336.1500 [m + h], found: 336.1471.
Embodiment 18
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2b (1.5 in the reaction tube of 25 ml Mmol, 210 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 Ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain white solid product 2,4- bis- (4- chlorphenyl) -9h- pyrimido [4,5-b] indole 3g(118 mg, 61%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is as follows:1h nmr (400 mhz, dmso-d 6) δ: 7.21 (t,j= 7.6 hz, 1h), 7.52 (t,j= 7.6 hz, 1h), 7.58-7.61 (m, 3h), 7.74 (d,j= 8.4 hz, 2h), 7.81 (d,j= 8.4 hz, 1h), 8.04 (d,j= 8.0 hz, 2h), 8.53 (d,j= 8.4 hz, 2h), 12.59 (s, 1h).13c nmr (100 mhz, dmso-d 6) δ: 109.6, 112.5, 119.1, 121.5, 122.5, 128.2, 129.1, 129.4, 130.0, 131.2, 135.4, 135.6, 137.3, 137.7, 139.7, 157.7, 158.3, 158.8. ms: m/z 390 [mh]+.
Embodiment 19
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2c (1.5 in the reaction tube of 25 ml Mmol, 277 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 Ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain white solid product 2,4- bis- (4- bromophenyl) -9h- pyrimido [4,5-b] indole 3h(150 mg, 63%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is as follows:1h nmr (400 mhz, dmso-d 6) δ: 7.22 (t,j= 7.6 hz, 1h), 7.52 (t,j= 8.0 hz, 1h), 7.59 (d,j= 7.6 hz, 1h), 7.74 (d,j= 8.0 hz, 2h), 7.81 (d,j= 8.4 hz, 1h), 7.88 (d,j= 8.4 hz, 2h), 7.97 (d,j= 8.0 hz, 2h), 8.46 (d,j= 8.8 hz, 2h), 12.60 (s, 1h).13c nmr (100 mhz, dmso-d 6) δ: 109.6, 112.6, 119.1, 121.5, 122.5, 124.1, 124.6, 128.3, 130.3, 131.5, 132.1, 132.3, 137.7, 138.0, 139.8, 157.7, 158.4, 158.9. ms: m/z 478 [mh]+.
Embodiment 20
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2d (1.5 in the reaction tube of 25 ml Mmol, 261 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 Ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain white solid product 2,4- bis- (4- trifluoromethyl) -9h- Pyrimido [4,5-b] indole 3i(107 mg, 47%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is such as Under:1h nmr (400 mhz, dmso-d 6) δ: 7.22 (t,j= 7.6 hz, 1h), 7.54 (t,j= 7.6 hz, 1h), 7.61 (d,j= 8.4 hz, 1h), 7.77 (d,j= 8.4 hz, 1h), 7.90 (d,j= 8.0 hz, 2h), 8.05 (d,j= 8.0 hz, 2h), 8.23 (d,j= 8.0 hz, 2h), 8.71 (d,j= 7.6 hz, 2h), 12.72 (s, 1h).13c nmr (100 mhz, dmso-d 6) δ: 110.3, 112.6, 118.8, 121.6, 122.6, 125.9, 126.0, 126.20, 126.23, 127.8, 128.0, 128.6, 128.8, 128.9, 130.2, 134.1, 140.0, 142.1, 142.7, 148.6, 157.6, 157.9, 158.4, 162.3. hrms calcd for c24h14f6n3: 458.1092 [m + h], found: 458.1077.
Embodiment 21
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2e in the reaction tube of 25 ml (1.5 mmol, 180 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), Trimethylace tonitric (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain white solid product 2,4- bis- (4- aminomethyl phenyl) -9h- Pyrimido [4,5-b] indole 3j(89 mg, 51%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is as follows :1h nmr (400 mhz, dmso-d 6) δ: 2.38 (s, 3h), 2.47 (s, 3h), 7.17 (t,j= 7.6 hz, 1h), 7.34 (d,j= 8.0 hz, 2h), 7.47-7.50 (m, 3h), 7.56 (d,j= 8.8 hz, 1h), 7.83 (d,j= 8.0 hz, 1h), 7.91 (d,j= 7.6 hz, 2h), 8.43 (d,j= 8.0 hz, 2h), 12.44 (s, 1h).13c nmr (100 mhz, dmso-d 6) δ: 21.5, 21.6, 109.1, 112.3, 119.5, 121.1, 122.3, 127.8, 128.3, 129.3, 129.6, 129.7, 136.0, 136.3, 139.5, 140.2, 140.4, 157.8, 159.7, 160.0. ms: m/z 350 [mh]+.
Embodiment 22
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2f (1.5 in the reaction tube of 25 ml Mmol, 204 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 Ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain white solid product 2,4- bis- (4- methoxyphenyl) -9h- phonetic Pyridine simultaneously [4,5-b] indole 3k(99 mg, 52%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is as follows:1h nmr (400 mhz, dmso-d 6) δ: 3.83 (s, 3h), 3.89 (s, 3h), 7.08 (d,j= 8.8 hz, 2h), 7.17 (t,j= 7.2 hz, 1h), 7.22 (d,j= 8.8 hz, 2h), 7.44-7.48 (m, 1h), 7.54 (d,j= 8.0 hz, 1h), 7.87 (d,j= 8.4 hz, 1h), 7.99 (d,j= 8.8 hz, 2h), 8.48 (d,j= 8.4 hz, 2h), 12.40 (s, 1h).13c nmr (100 mhz, dmso-d 6) δ: 55.7, 55.8, 108.4, 112.2, 114.3, 114.5, 119.6, 121.0, 122.2, 127.5, 129.9, 130.9, 131.1, 131.4, 139.3, 157.8, 159.3, 159.7, 161.2, 161.6. ms: m/z 382 [mh]+.
Embodiment 23
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2g in the reaction tube of 25 ml (1.5 mmol, 186 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), Trimethylace tonitric (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain white solid product 2,4- bis- (3- fluorophenyl) -9h- phonetic Pyridine simultaneously [4,5-b] indole 3l(103 mg, 58%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is as follows:1h nmr (400 mhz, dmso-d 6) δ: 7.19-7.23 (m, 1h), 7.32-7.37 (m, 1h), 7.47-7.56 (m, 2h), 7.58-7.61 (m, 2h), 7.70-7.82 (m, 3h), 7.86 (d,j= 7.6 hz, 1h), 8.21-8.24 (m, 1h), 8.38 (d,j= 7.6 hz, 1h). 12.65 (s, 1h).13c nmr (100 mhz, dmso-d 6) δ: 109.8, 112.6, 114.5, 114.7, 116.0, 116.2, 117.3, 117.46, 117.54, 117.7, 118.9, 121.5, 122.4, 124.3, 125.5, 128.4, 131.1, 131.2, 131.3, 131.4, 139.8, 140.9, 141.0, 141.1, 141.2, 157.6, 158.0, 158.5, 161.6, 161.8, 164.0, 164.2. hrms calcd for c22h14f2n3: 358.1156 [m + h], found: 358.1142.
Embodiment 24
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2h (1.5 in the reaction tube of 25 ml Mmol, 180 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), front three Guanidine-acetic acid (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 Ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain white solid product 2,4- bis- (3- aminomethyl phenyl) -9h- pyrimidine And [4,5-b] indole 3m(92 mg, 53%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is as follows:1h nmr (400 mhz, dmso-d 6) δ: 2.42 (s, 3h), 2.47 (s, 3h), 7.16-7.20 (m, 1h), 7.32 (d,j= 8.0 hz, 1h), 7.40-7.51 (m, 3h), 7.56 (t,j= 7.6 hz, 2h), 7.77-7.79 (m, 3h), 8.33-8.35 (m, 2h), 12.50 (s, 1h).13c nmr (100 mhz, dmso-d 6) δ: 21.53, 21.66, 109.4, 112.4, 119.4, 121.2, 122.3, 125.6, 126.4, 127.9, 128.87, 128.93, 129.1, 129.8, 131.0, 131.4, 138.1, 138.5, 138.6, 139.1, 139.6, 157.7, 159.9, 160.0. hrms calcd for c24h20n3: 350.1657 [m + h], found: 350.1669.
Embodiment 25
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2i in the reaction tube of 25 ml (1.5 mmol, 180 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), Trimethylace tonitric (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain white solid product 2,4- bis- (2- aminomethyl phenyl) -9h- Pyrimido [4,5-b] indole 3n(84 mg, 48%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is as follows :1h nmr (400 mhz, cdcl3) δ: 2.31 (s, 3h), 2.62 (s, 3h), 6.14 (d,j= 7.6 hz, 1h), 7.06 (t,j= 7.6 hz, 1h), 7.21 (t,j= 8.0 hz, 1h), 7.25-7.26 (m, 1h), 7.37-7.51 (m, 6h), 7.55 (d,j= 7.2 hz, 1h), 7.92 (d,j= 7.2 hz, 1h), 12.86 (s, 1h).13c nmr (100 mhz, cdcl3) δ: 19.6, 20.6, 111.1, 111.8, 119.3, 121.1, 122.1, 126.1, 126.3, 127.4, 128.9, 129.0, 129.2, 130.5, 130.7, 131.2, 135.9, 137.0, 137.9, 138.8, 139.6, 156.8, 160.7, 162.9. ms: m/z 350 [mh]+.
Embodiment 26
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2j in the reaction tube of 25 ml (1.5 mmol, 234 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), Trimethylace tonitric (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain white solid product 2,4- dinaphthyl -9h- pyrimido [4,5-b] indole 3o(97 mg, 46%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is as follows:1h nmr (400 mhz, dmso-d 6) δ: 6.81 (d,j= 8.0 hz, 1h), 6.97 (t,j= 7.6 hz, 1h), 7.44 (t,j= 8.0 hz, 2h), 7.52-7.55 (m, 2h), 7.58 (t,j= 7.6 hz, 2h), 7.65 (t,j= 7.6 hz, 1h), 7.75-7.78 (m, 2h), 7.88 (d,j= 7.2 hz, 1h), 7.99-8.02 (m, 1h), 8.05 (d,j= 8.4 hz, 1h), 8.11 (d,j= 8.4 hz, 1h), 8.17-8.21 (m, 2h), 8.88-8.90 (m, 1h), 12.68 (s, 1h).13c nmr (100 mhz, cdcl3) δ: 111.5, 112.1, 119.1, 121.0, 122.6, 123.6, 125.4, 125.57, 125.62, 125.9, 126.1, 126.2, 126.8, 127.0, 127.3, 128.4, 128.50, 128.52, 129.2, 129.9, 130.7, 131.5, 133.8, 134.2, 135.9, 137.2, 138.7, 157.0, 159.8, 162.4. hrms calcd for c30h20n3: 422.1657 [m + h], found: 422.1642.
Embodiment 27
Method as described in embodiment 1, adds 1a (0.5 mmol, 170 mg), 2k in the reaction tube of 25 ml (1.5 mmol, 168 mg), Hydro-Giene (Water Science). (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), Trimethylace tonitric (0.5 mmol, 51 mg) and n, n- dimethylformamide (3 ml), be subsequently adding strong aqua ammonia (7 mmol, 0.5 ml).It is heated to 80 DEG C under air, after stirring 30 hours, obtain white solid product 2,4- dithienyl -9h- pyrimido [4,5-b] indole 3p(67 mg, 40%) (petrol ether/ethyl acetate=10/1).The characterize data of this compound is as follows:1h nmr (400 mhz, dmso-d 6) δ: 7.21-7.24 (m, 1h), 7.28 (t,j= 7.6 hz, 1h), 7.38-7.40 (m, 1h), 7.50-7.57 (m, 2h), 7.74 (d,j= 5.6 hz, 1h), 7.95 (d,j= 4.8 hz, 1h), 7.99-8.00 (m, 1h), 8.13 (d,j= 4.0 hz, 1h), 8.28 (d,j= 8.0 hz, 1h), 12.59 (s, 1h).13c nmr (100 mhz, dmso-d 6) δ: 107.6, 112.4, 119.3, 121.5, 122.4, 128.0, 128.7, 128.8, 128.9, 129.8, 130.6, 131.2, 139.5, 142.3, 144.1, 152.9, 156.5, 157.8. hrms calcd for c18h12n3s2: 334.0472 [m + h], found: 334.0460.
Embodiment above describes ultimate principle, principal character and the advantage of the present invention.The technical staff of the industry should Understand, the present invention is not restricted to the described embodiments, the simply explanation present invention's described in above-described embodiment and description is former Reason, under the scope without departing from the principle of the invention, the present invention also has various changes and modifications, and these changes and improvements each fall within In the scope of protection of the invention.

Claims (2)

1. one kind 9h- pyrimido [4,5-b] Benzazole compounds synthetic method it is characterised in that: by bromo- for 1- 2-(2,2- bis- Bromo vinyl) benzene or derivatives thereof 1, ammonia and aldehyde compound 2 be dissolved in organic solvent, is subsequently adding catalyst transition metal Salt and additive, are obtained 9 in 60-100 DEG C of reaction in the presence of the airh- pyrimidine [4,5-b] Benzazole compounds 3, this synthesis Reaction equation in method is:
,
Wherein r1For hydrogen, fluorine, chlorine, trifluoromethyl, methyl or methoxy, r2For 1- naphthyl, 2- thienyl, phenyl or substituted-phenyl, Substituent group on this substituted-phenyl phenyl ring is one or more of fluorine, chlorine, bromine, methyl, trifluoromethyl or methoxyl group, substituent group Position be phenyl ring on ortho position, meta or para position, organic solvent be dimethyl sulfoxide, n, n- dimethylformamide, methyl pyrrole Pyrrolidone, isopropanol or dioxane, catalyst transition metal salt be Cu-lyt., cuprous bromide, Hydro-Giene (Water Science)., copper acetate or Copper chloride, additive is one or more of 1,10- phenanthroline, l- proline, triethylene diamine or trimethylace tonitric.
2. according to claim 19h- pyrimido [4,5-b] Benzazole compounds synthetic method it is characterised in that: Described 1- bromo- 2-(2,2- dibromo vinyl) benzene or derivatives thereof, ammonia and aldehyde compound the amount of the material that feeds intake ratio For 1:7-42:2-3.
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